We have employed two genome technologies in Saccharomyces cerevisiae to determine the cellular impact and possible mechanisms involved in arsenic toxicity and carcinogenicity. By combining transcript profiling with the screening of a comprehensive panel of bar-coded deletion strains, we have identified the genes and pathways most affected by this metalloid. Each data set was mapped to a metabolic network composed of all known biochemical reactions in yeast, as well as, the yeast netowrk of 20,985 protein-protein and protein-DNA interactions.. This analysis indicated that arsenic likely channels sulfur into glutathione for detoxification, leads to indirect oxidative stress by depleting glutathione pools, and alters protein turnover via arsenation of sulfhydryl groups on proteins. Further profiling of specific deletion strains confirmed that the transcription factors Yap1, Arr1 (Yap8), and Rpn4 strongly mediated the cell?s adaptation to arsenic-induced stress but that, surprisingly, Cad1 (Yap2) had negligible impact. Contrary to the gene expression analyses, the phenotypic profiling data mapped to the metabolic network. The two significant metabolic networks unveiled were shikimate and serine, threonine, and glutamate biosynthesis. These phenotypically sensitive pathways were upstream of differentially expressed ones, indicating that transcriptional and phenotypic profiling implicate distinct, but related pathways.